Autosomal Recessive Alport Syndrome Unveiled by Pregnancy

Abstract

Alport syndrome is a hereditary disease affecting Type IV collagen characterized by hematuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities. Most cases are X-linked and involve the <i>COL4A5</i> gene with a minority of patients having autosomal recessive mutations in the <i>COL4A3</i> or <i>COL4A4</i> genes encoding the α3(IV) or α4(IV) chain respectively. Here, we describe the case of a 31-year-old woman who presented during pregnancy with hematuria and proteinuria and was diagnosed with autosomal recessive Alport syndrome (ARAS) post-partum. Her biopsy was notable for findings of segmental glomerulosclerosis with some collapsing features, in addition to thin basement membranes and rare “splitting”. Genetic testing identified 2 novel mutations in the <i>COL4A4</i> gene: a truncating frame shift mutation c.3861delinsCTC and a missense mutation c.4708G>A (p.Glu1570Lys), both of which we assert to be pathogenic. She had normal full-term delivery without complications. This case has several unique features including the relatively mild disease phenotype and the findings of glomerular scarring with collapsing features on renal biopsy. The successful pregnancy outcome and her clinical presentation add to the growing body of evidence that ARAS can have a variable phenotype.

Case Report: Preimplantation Genetic Testing and Pregnancy Outcomes in Women With Alport Syndrome

“…Thirty pregnancies in different types of Alport syndrome had been reported in 20 cases ( Matsuo et al, 2007 ; Zhang et al, 2007 ; Matsubara et al, 2009 ; Fabris et al, 2012 ; Matsubara and Muto, 2012 ; Saifan et al, 2012 ; Crovetto et al, 2013 ; Mehta et al, 2013 ; Alessi et al, 2014 ; Gerasimovska Kitanovska et al, 2016 ; Nishizawa et al, 2016 ; Yefet et al, 2016 ; Brunini et al, 2018 ; Drury et al, 2019 ; Supplementary Table 3 ). Most of the reported cases presented with normal blood pressure and renal function before conception.…”

A Novel Homozygous Mutation in the COL4A4 Gene (Gly1436del) Causing Alport Syndrome Exposed by Pregnancy: A Case Report and Review of the Literature

“…In another case report of ARAS caused by a Col4A4 mutation with manifestation during pregnancy, Drury et al described the histological presentation of their patient as global segmental glomerulosclerosis with collapsing features, which might be caused by the additive effect of hyperfiltration during pregnancy [6]. Generally, the literature review shows an association of collagen IV mutations with segmental sclerosis [5,16], which may lead to misdiagnosis of collagen IV nephropathies as FSGS [6]. e present case report is intended to raise awareness of atypical courses of AS and emphasizes the importance of medical family history and genetic testing in such cases.…”

“…At present, our patient's AS presents exclusively with significant renal involvement. Interestingly, in ARAS females, ocular and inner ear involvement is only present in a minority of patients [ 6 , 10 ]. Basically, genotype-phenotype correlation in AS is variable.…”

“…Histologically, AS presented as segmental sclerosis in this case. In another case report of ARAS caused by a Col4A4 mutation with manifestation during pregnancy, Drury et al described the histological presentation of their patient as global segmental glomerulosclerosis with collapsing features, which might be caused by the additive effect of hyperfiltration during pregnancy [ 6 ]. Generally, the literature review shows an association of collagen IV mutations with segmental sclerosis [ 5 , 16 ], which may lead to misdiagnosis of collagen IV nephropathies as FSGS [ 6 ].…”

“…In women, the first clinical manifestation of AS may appear as nephrotic syndrome during pregnancy, as pregnancy-related hyperfiltration may acutely worsen renal function [ 6 , 7 ]. However, due to the unspecific and variably graded clinical manifestations and the possible progression towards a renal phenotype with histological patterns of more common glomerular entities associated with proteinuria, AS remains a highly under- or misdiagnosed entity [ 4 ].…”